Patients with HIV infection who have AIDS are subject to an unexplained dementia even though virus is not observed in the brain. It is proposed that a soluble factor released from the virus may be affecting patients. We find that the HIV viral protein Tat promotes neural cell adhesion in vitro and blocks laminin-mediated process outgrowth. These events are mediated by a 90 kDa Tat receptor and were localized to a 9 amino acid sequence in Tat. Direct injection of Tat into the brains of rats caused impaired motor function and destruction of large amounts of brain tissue. High doses resulted in death. These data demonstrate that Tat has a strong effect on neural cells and suggest a possible mechanism to explain the neurologic changes and dementia observed in patients with AIDS. Infection of T cells with HIV-1 stimulated invasiveness through basement membrane, and synthesis of the 92 kDa type IV collagenase (gelatinase B). Monocyte infection by HIV-1 resulted in substantial increases in cell-cell adhesion mediated primarily by the integrin alphabetaLbeta2. Increased adhesion of HIV-infected monocytes to a variety of endothelial cell types was followed by marked disruption of endothelial cell layers and increased vascular permeability, accompanied by increased expression of the 92 kDa metalloproteinase gelatinase B. This endothelial disruption was inhibited strongly by protease inhibitors including the TIMPs. These findings suggest the hypothesis that HIV-1 infection may activate blood monocytes to adhere to endothelium in aggregates, then to secrete increased amounts of protease activity resulting in endothelial disruption, thereby permitting invasion of HIV-infected cells into tissues. In preliminary studies, the HIV product Tat by itself induced secretion of the 92 kDa gelatinase B in dose-dependent fashion. These novel findings may provide a mechanism for metalloproteinase induction in HIV-infected cells, and they suggest that creative new approaches using specific metalloproteinase inhibitors to block tissue invasion might ultimately provide new insights into AIDS pathogenesis and preventive therapy.